Classification of H2O2 as aNeuromodulator that Regulates Striatal Dopamine Release on a SubsecondTime Scale

摘要

Here we review evidence that the reactive oxygen species, hydrogen peroxide (H2O2), meets the criteria for classification as a neuromodulator through its effects on striatal dopamine (DA) release. This evidence was obtained using fast-scan cyclic voltammetry to detect evoked DA release in striatal slices, along with whole-cell and fluorescence imaging to monitor cellular activity and H2O2 generation in striatal medium spiny neurons (MSNs). The data show that (1) exogenous H2O2 suppresses DA release in dorsal striatum and nucleus accumbens shell and the same effect is seen with elevation of endogenous H2O2 levels; (2) H2O2 is generated downstream from glutamatergic AMPA receptor activation in MSNs, but not DA axons; (3) generation of modulatory H2O2 is activity dependent; (4) H2O2 generated in MSNs diffuses to DA axons to cause transient DA release suppression by activating ATP-sensitive K⁺ (KATP) channels on DA axons; and (5) the amplitude of H2O₂-dependent inhibition of DA release is attenuated by enzymatic degradation of H₂O₂, but the subsecond time course is determined by H₂O₂ diffusion rate and/or K_ATP-channelkinetics. In the dorsal striatum, neuromodulatory H₂O₂ is an intermediate in the regulation of DA release by theclassical neurotransmitters glutamate and GABA, as well as other neuromodulators,including cannabinoids. However, modulatory actions of H₂O₂ occur in other regions and cell types, as well, consistentwith the widespread expression of K_ATP and other H₂O₂-sensitive channels throughout the CNS.